Approach to Polyneuropathies

Axonal vs Demyelinating NCS Features

Initial (First-Tier) Evaluation

Second-Tier (Directed by First-Tier Results / Phenotype)

• CSF analysis — for suspected GBS, CIDP, paraneoplastic, infectious, or carcinomatous polyradiculoneuropathy
• NCS / EMG — classify axonal vs demyelinating; identify conduction block, asymmetry, mononeuritis multiplex pattern
• Skin punch biopsy (IENFD) — for suspected small fiber neuropathy with normal NCS
• Genetic testing — CMT panel, hATTR (TTR sequencing) if hereditary suspected (family history, foot deformities, palpable nerves, very slow CV)
• Nerve biopsy (sural) — for suspected vasculitis, amyloidosis, sarcoid, or unexplained progressive neuropathy after non-invasive workup; not first-line
• Paraneoplastic antibody panel — for subacute sensory neuronopathy or rapidly progressive painful neuropathy (anti-Hu, anti-CV2/CRMP5)
• Heavy metal screen / toxicology — only when exposure history or characteristic clues (Mees’ lines, alopecia, wristdrop)
• Imaging — nerve ultrasound or MR neurography (CIDP, MMN, tumor infiltration); FDG-PET / whole-body CT (POEMS, paraneoplastic)

GBS Subtypes

Clinical Features & Diagnosis

• Preceding infection: 2/3 of cases; Campylobacter jejuni is most common (30%) — associated with AMAN & anti-GM1; also CMV, EBV, Mycoplasma, Zika, COVID
• Classic presentation: ascending symmetric weakness + areflexia over days to 4 weeks; nadir by 4 weeks (if >8 weeks → consider CIDP)
• Facial weakness: bilateral in ~50%; back pain and neuropathic pain are common early symptoms
• Autonomic dysfunction: tachycardia, bradycardia, BP lability, urinary retention, ileus — leading cause of death in ICU
• CSF: albuminocytological dissociation — elevated protein with normal cell count (≤5 cells/μL); may be normal in first week
• If CSF WBC >50 → think HIV, Lyme, sarcoid, CMV polyradiculopathy, carcinomatous meningitis

Electrodiagnostic Findings

• Earliest finding: absent or prolonged H-reflexes and F-waves (most sensitive in week 1)
• Sural sparing pattern: absent or reduced upper extremity SNAPs with preserved sural SNAP — highly specific for AIDP
• NCS may be normal in the first 1–2 weeks; repeat at 2–3 weeks if initial study is normal
• AIDP: prolonged distal latencies, slow CV, conduction block, temporal dispersion, prolonged F-waves
• AMAN: low CMAPs, normal SNAPs, normal velocities — early reversible conduction failure may mimic demyelination

Respiratory Monitoring — The 20/30/40 Rule

• Erasmus GBS Respiratory Insufficiency Score (EGRIS): predicts need for mechanical ventilation using onset-to-admission interval, facial/bulbar weakness, and MRC sum score
• Monitor FVC every 4–6 hours in progressive GBS; do NOT rely on oxygen saturation (late finding)

Treatment

Poor Prognostic Factors

• Age >60, preceding Campylobacter infection, rapid onset (<7 days to unable to walk)
• Need for mechanical ventilation, low CMAP amplitudes (axonal damage), AMAN/AMSAN subtype
• High modified Erasmus GBS Outcome Score (mEGOS) at day 7
• ~5% mortality even with treatment; ~20% still unable to walk at 6 months

Diagnostic Criteria

• Timeline: onset ≥8 weeks progressive or relapsing course (vs GBS which peaks by 4 weeks)
• Pattern: symmetric proximal AND distal weakness (proximal involvement distinguishes from most other neuropathies)
• Reflexes: absent or reduced in all limbs
• CSF: protein typically elevated (often >100 mg/dL); WBC <10/μL per EFNS/PNS 2021
• NCS (must meet criteria): multifocal demyelination with at least 2 of: prolonged distal motor latencies, slow CV, prolonged F-waves, conduction block, temporal dispersion — in ≥2 nerves
• Nerve biopsy: onion bulb formation (concentric Schwann cell layers from repeated de/remyelination); not required for diagnosis but supportive

CIDP vs GBS

CIDP Variants

Treatment

• First-line: IVIg (2 g/kg over 2–5 days, then 1 g/kg maintenance every 3–4 weeks), corticosteroids, or PE
• Key difference from GBS: steroids are effective and are first-line for CIDP
• Second-line: azathioprine, mycophenolate, cyclosporine, rituximab
• Subcutaneous Ig (SCIg): Hizentra approved 2018; HyQvia approved 2024 — FDA-approved for CIDP maintenance; equivalent efficacy to IVIG with fewer systemic effects
• >90% respond to at least one first-line agent; ~50% require long-term immunotherapy

Overview

• Pattern: pure motor, asymmetric, upper-limb predominant weakness (often begins in distal arm — wristdrop, fingerdrop, grip weakness)
• Course: slowly progressive over years; preserved sensation; reflexes reduced or absent in affected nerve distributions
• No upper motor neuron signs (vs ALS); fasciculations and cramps may be present (mimics ALS lower motor neuron presentation)

Electrodiagnostic Features

• Conduction block at non-entrapment sites on motor NCS — the diagnostic hallmark
• Normal sensory NCS through the segments of motor conduction block (key distinguishing feature from MADSAM/Lewis-Sumner)
• Distal CMAP amplitudes preserved with proximal drop >50% (definite conduction block)
• EMG: chronic neurogenic changes in weak muscles (reinnervation MUAPs, reduced recruitment)

Antibodies & Diagnosis

• Anti-GM1 IgM antibodies in ~50% of cases (supportive but not required for diagnosis)
• CSF protein is usually normal or only mildly elevated (vs CIDP where protein is markedly elevated)
• EFNS/PNS criteria require conduction block in ≥1 nerve outside common entrapment sites

Treatment

• IVIG is the only effective therapy (FDA-approved); typical regimen 2 g/kg over 2–5 days, then maintenance every 2–6 weeks
• Steroids and plasma exchange WORSEN MMN or are ineffective — critical distinction from CIDP
• Second-line (refractory cases): cyclophosphamide, rituximab
• SCIg increasingly used for maintenance

Overview

• Per EFNS/PNS 2021, nodal/paranodal antibody neuropathies are classified separately from CIDP — distinct pathophysiology targeting nodal/paranodal proteins, and often respond poorly to IVIg
• Many are IgG4-mediated (especially NF155, CNTN1, CASPR1 phenotypes) — IgG4 does not fix complement, which helps explain the poor IVIg response; antibody subclass varies by target and case
• Rituximab is commonly used (B-cell depletion reduces IgG4 production), but the supporting evidence is largely observational; optimal treatment varies by antibody target and clinical phenotype
• Nerve biopsy may show node/paranode disruption without true demyelination

Specific Antibodies

Classification of Diabetic Neuropathies

Small Fiber vs Large Fiber Neuropathy

Charcot-Marie-Tooth Classification

HNPP and Dejerine-Sottas

Hereditary vs Acquired Demyelination

Overview

• Genetics: autosomal dominant point mutations in TTR gene (most common: Val30Met in endemic foci — Portugal, Sweden, Japan; Val122Ile in African-American population)
• Pathology: mutated transthyretin protein misfolds and deposits as amyloid fibrils in peripheral nerve, heart, kidney, GI tract
• Phenotype: length-dependent painful small fiber + autonomic neuropathy progressing to large fiber sensorimotor; rapidly progressive; cardiomyopathy (restrictive); GI dysmotility; vitreous amyloid in some mutations
• Bilateral CTS is more characteristic of ATTR (hereditary and wild-type) than AL amyloid — often precedes systemic disease by years

Diagnosis

• TTR gene sequencing (definitive)
• Tissue biopsy (nerve, fat pad, salivary gland, or cardiac) with Congo red birefringence + mass spectrometry typing (distinguishes TTR vs AL vs wild-type ATTR)
• Bone scintigraphy (^99mTc-PYP / DPD / HMDP) — highly sensitive/specific for cardiac ATTR; can establish diagnosis non-invasively when monoclonal protein is excluded

FDA-Approved Therapies for hATTR Polyneuropathy (U.S.)

Bottom line: For U.S. hATTR polyneuropathy, disease-modifying therapy = TTR knockdown (patisiran, vutrisiran, inotersen, eplontersen). TTR stabilizers (tafamidis, acoramidis) are FDA-approved for ATTR cardiomyopathy (ATTR-CM) in the U.S., NOT for polyneuropathy; tafamidis has polyneuropathy approval in some non-U.S. regions (EU).

HSAN Subtypes

Overview

• Genetics: autosomal recessive ABCA1 mutation (9q31) → defective cellular cholesterol efflux → cholesteryl ester accumulation in macrophages and Schwann cells.
• Biochemical signature: markedly low HDL (often near 0) and low total cholesterol; LDL normal-to-low; triglycerides normal-to-elevated.
• Classic triad: peripheral neuropathy + enlarged orange/yellow tonsils + low HDL.

Neuropathy Phenotypes

• Pseudosyringomyelic pattern (most distinctive): cape-like dissociated sensory loss (pain/temp lost, large-fiber preserved) with facial & upper-limb weakness — mimics syringomyelia.
• Asymmetric multifocal mononeuropathy multiplex pattern, or distal sensorimotor pattern with face involvement.
• Schwann cell lipid accumulation visible on nerve biopsy.

Systemic Features & Treatment

• Hepatosplenomegaly, premature atherosclerosis (despite low LDL), corneal opacities; thrombocytopenia possible.
• No specific therapy — manage cardiovascular risk and supportive neuropathy care.

Overview

• Antibody: anti-Hu (ANNA-1) — targets HuD antigen in neuronal nuclei (dorsal root ganglia, sympathetic ganglia, enteric neurons, brain)
• Cancer association: small cell lung cancer (SCLC) in >80%; less commonly neuroblastoma, prostate, breast
• Clinical presentation: subacute (weeks to months) asymmetric sensory loss with prominent sensory ataxia; non-length-dependent (face, trunk, arms involved early); pseudoathetosis
• Motor function preserved (DRG — sensory neuron — is the target); reflexes lost due to deafferentation; all sensory modalities affected (small and large fiber)
• May overlap with other paraneoplastic syndromes: limbic encephalitis, cerebellar degeneration, autonomic failure (enteric neuropathy → gastroparesis, pseudo-obstruction)

Diagnosis

• Serum/CSF anti-Hu antibodies (high titer in serum; CSF positive supports CNS involvement)
• CSF: mild lymphocytic pleocytosis, elevated protein, oligoclonal bands may be present
• NCS: absent or markedly reduced SNAPs (all distributions) with preserved CMAPs — pure sensory neuronopathy pattern
• MRI spinal cord: T2 hyperintensity in dorsal columns (Wallerian degeneration from DRG cell death)
• Cancer screening: chest CT, FDG-PET; repeat at 3–6 month intervals if initially negative

Treatment

• Treat underlying cancer (most effective therapy) — often the only intervention that stabilizes the neuropathy
• Immunotherapy (IVIG, steroids, rituximab, cyclophosphamide) has limited benefit because DRG neuron death is rapid and irreversible
• Early diagnosis (before neuronal loss) is critical — the neuropathy typically precedes cancer detection by months

Overview

• Definition: selective involvement of small myelinated (Aδ) and unmyelinated (C) fibers
• Symptoms: burning/stinging pain (feet > hands), allodynia, hyperalgesia; autonomic features (dry eyes/mouth, GI dysmotility, orthostatic intolerance, sweating abnormalities)
• Exam: reduced pinprick and temperature sensation in stocking distribution; preserved vibration, proprioception, and reflexes; strength normal
• NCS/EMG: completely normal (standard NCS only tests large fibers)

Diagnosis

Etiologies

Drug-Induced Neuropathies

Heavy Metal Neuropathies

Nutritional & Metabolic Neuropathies

Overview

• Pattern: mononeuritis multiplex (asymmetric involvement of individual named nerves) that may evolve into confluent distal symmetric pattern
• Mechanism: necrotizing vasculitis of vasa nervorum → ischemic axonal damage
• NCS/EMG: multifocal axonal neuropathy; asymmetric SNAP/CMAP reductions in individual nerve territories
• Diagnosis: sural nerve biopsy — epineurial necrotizing vasculitis with transmural inflammatory infiltrate and fibrinoid necrosis

Causes of Vasculitic Neuropathy

Treatment

• Systemic vasculitis: high-dose corticosteroids + cyclophosphamide for induction; azathioprine or methotrexate for maintenance
• NSVN: corticosteroids alone may suffice; add cyclophosphamide if progressive
• Rituximab: increasingly used as alternative to cyclophosphamide in ANCA-associated vasculitis (RAVE and RITUXVAS trials)

Overview

POEMS Syndrome

• Polyneuropathy — demyelinating, motor ≥ sensory; mandatory criterion; mimics CIDP but does NOT respond to IVIg
• Organomegaly — hepatosplenomegaly, lymphadenopathy
• Endocrinopathy — hypogonadism, hypothyroidism, adrenal insufficiency, diabetes
• M-protein — IgA or IgG with lambda restriction in >95% of cases; kappa POEMS is rare but reported
• Skin changes — hyperpigmentation, hypertrichosis, hemangiomas, white nails
• Other features: elevated VEGF (best marker for disease activity), papilledema, edema/ascites/pleural effusion, thrombocytosis, polycythemia
• Sclerotic bone lesions: osteosclerotic (vs lytic in myeloma) — FDG-PET or whole-body CT for screening
• Treatment: radiation if solitary plasmacytoma; autologous stem cell transplant if disseminated

First-Line Agents

Second-Line / Adjunctive

• Tramadol — weak opioid + SNRI activity; risk of serotonin syndrome with other serotonergic agents; lowers seizure threshold
• Topical capsaicin 8% patch — for localized neuropathic pain; FDA-approved for postherpetic neuralgia and DPN of the feet
• Topical lidocaine 5% patch — well-tolerated; minimal systemic absorption
• Opioids — avoid as first-line; reserve for refractory pain after multimodal failure

Refractory / Interventional

• Spinal cord stimulation — FDA-approved for painful diabetic neuropathy refractory to medical therapy (10 kHz high-frequency SCS shown effective in SENZA-PDN trial)
• Dorsal root ganglion stimulation for focal neuropathic pain syndromes

Critical Illness Polyneuropathy (CIP) vs Critical Illness Myopathy (CIM)

Key Diagnostic Points

• Presentation: difficulty weaning from ventilator + diffuse limb weakness in a septic ICU patient → think CIP/CIM
• Most sensitive early NCS finding: reduced CMAP amplitudes (both CIP and CIM)
• Key distinguishing test: SNAPs — reduced in CIP, preserved in CIM
• Combined CIP/CIM (CIPNM): most patients have overlap; reduced CMAPs + reduced SNAPs + myopathic EMG
• Treatment: no specific therapy; treat underlying sepsis/organ failure; minimize steroids and NMB agents; early mobilization; supportive care
• Prevention: avoid hyperglycemia (early van den Berghe data suggested benefit, but NICE-SUGAR showed harm from very tight control); current target ~140–180 mg/dL; early mobilization; minimize sedation